Glioblastoma (GBM) is the most common and most aggressive of the primary malignant brain tumor in adults, with a median overall survival of 19.6 months following multi-modality therapy. The main limiting factor in delivering a tumoricidal radiation dose is the toxicity to surrounding brain. Therapeutic radionuclides, due to a short tissue path and differences in radiobiology, have the potential to extend the therapeutic window for radiation in GBM. However, a carrier is needed to deliver the isotope to the brain and maintain its localization at the desired site, as otherwise they quickly disperse. Liposomal encapsulation has the potential to facilitate radioisotope retention within the tissue, but a method for the efficient loading of liposomes with the radioisotopes was needed. This has been an essential limiting factor in the development of this technology, and has now been successfully addressed. To overcome this, we have developed an encapsulation method using a custom lipophilic molecule (BMEDA) that carries the rhenium radionuclides into the aqueous compartment of the liposome nanoparticles. The final investigational product is Rhenium nanoliposomes (186RNL). To characterize the retention, tolerability, and activity of 186RNL, we performed intratumoral infusions of 186RNL in rats bearing glioblastoma tumors. Increasing doses as high as 30-fold typical external beam doses consistently showed that animals tolerated all doses without evidence of harm, and were associated with marked survival differences. In addition, many of the rats had no residual tumor. A toxicity study was performed in beagles with 186RNL or blank control nanoliposomes and produced no significant changes systemically or in the brains of dogs at 24 hours or 14 Days. In order to further characterize the drug product and address chemistry, manufacturing, and control concerns of FDA, we entered into a collaborative agreement with the Nanotechnology Characterization Laboratory (NCL) of the National Cancer Institute (NCI). NCL was provided with manufacturing protocols, reagents, and representative lots manufactured at the UTHSA. No significant difference was observed between RNL manufactured at the two sites and with marked stability of final product observed. The drug was cleared by the FDA to proceed to clinical study shortly thereafter. It is our specific hypothesis that 186RNL can safely be administered to patients with recurrent progressive GBM at much higher radiation doses than can be achieved with current techniques, and that treatment with 186RNL will markedly improve survival in GBM patients. Continued clinical development is warranted. We therefore propose to test the maximum tolerable dose and safety profile of 186RNL in patients with recurrent glioma, determine the efficacy of 186RNL in recurrent glioblastoma, and to develop and validate a mathematical model to predict the distribution of 186RNL. The immediate goal of this Aim is to use early time point, patient-specific data, to calibrate a mechanism-based model, thereby allowing for the accurate prediction of the distribution of 186RNL as a function of time. This model will be developed using data established in Aim 1, then used before delivery of 186RNL in the selection of the optimal point of injection in in Aim 2.